Andreas Grüneisen

Age-Related Risk Profile and Chemotherapy Dose Response in Acute Myeloid Leukemia: A Study by the German Acute Myeloid Leukemia Cooperative Group

PURPOSE The purpose of the study was to assess the contribution of age and disease variables to the outcome of untreated patients with acute myeloid leukemia (AML) receiving varying intensive induction chemotherapy. PATIENTS AND METHODS Patients 16 to 85 years of age with primary AML, known karyotype, and uniform postremission chemotherapy enrolled onto two consecutive trials were eligible and were randomly assigned to induction either with a standard-dose (cytarabine, daunorubicin, and 6-thioguanine) and a high-dose (cytarabine and mitoxantrone) combination, or with two courses of the high-dose combination. Subgroups were defined by karyotype, nucleophosmin and FLT3 mutation, WBC count, serum lactate dehydrogenase, and residual blasts. RESULTS In 1,284 patients, the overall survival at 4 years in those younger and older than 60 years was 37% versus 16% (P < .001) and the ongoing remission duration was 46% versus 22% (P < .001). Similar age-related differences in outcome were found for all defined subgroups. No difference in outcome according to randomly assigned treatment regimen was observed in any age group or prognostic subset. Regarding prognostic subgroups, molecular factors were also considered. CONCLUSION Under harmonized conditions, older and younger patients with AML show modest differences in their risk profiles and equally no dose response to intensified chemotherapy. Their observed fundamental difference in outcome across all subgroups remains unexplained. Further molecular investigation may elucidate the age effect in AML and identify new targets.

High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG.

The objective of this study for newly diagnosed acute promyelocytic Leukemia (APL) was to evaluate the efficacy of an intensified double induction chemotherapy including high dose ara-C (HD) and all-trans retinoic acid (ATRA) followed by consolidation and 3 years maintenance therapy. In contrast to APL studies stratifying therapy according to pretreatment white blood cell (WBC) count < and ⩾10 × 109/l (low/intermediate and high risk according to the Sanz score), our patients received uniform therapy. From 1994 to 2005, 142 patients (age, 16–60 years) were enrolled. In the low/intermediate (n=105) vs high (n=37) WBC group, the rates of complete remission were 95.2 vs 83.8%, of induction death were 4.8 vs 16.2% (P=0.05) and of molecular remission were 87.5 vs 91.3% (P=1). Long-term overall survival was 84.4 vs 73.0% (P=0.12), event free survival was 78.3 vs 67.3% (P=0.11), relapse free survival was 82.1 vs 80.0% (P=0.83) and the cumulative incidence of relapse was 7.4 vs 11.4% (P=0.46). No relapse or death occurred after 4.7 years. ATRA and intensified chemotherapy including HD ara-C followed by prolonged maintenance therapy reduced the relapse risk in high risk patients. Pretreatment WBC count ⩾10 × 109/l count was no relevant prognostic factor for relapse.

Dose-dense induction with sequential high-dose cytarabine and mitoxantone (S-HAM) and pegfilgrastim results in a high efficacy and a short duration of critical neutropenia in de novo acute myeloid leukemia: a pilot study of the AMLCG

Dose density during early induction has been demonstrated to be one of the prime determinants for treatment efficacy in acute myeloid leukemia (AML). The German AML Cooperative Group has therefore piloted a dose-dense induction regimen sequential high-dose AraC and mitoxantrone followed by pegfilgrastim (S-HAM) in which 2 induction cycles are applied over 11 to 12 days instead of 25 to 29 days as used in conventional double induction, thereby increasing dose density 2-fold. Of 172 de novo AML patients (excluding acute promyelocytic leukemia), 61% reached a complete remission, 22% a complete remission with incomplete peripheral recovery, 7% had persistent leukemia, 10% died (early death) resulting in an overall response rate of 83%. Kaplan-Meier estimated survival at 2 years was 61% for the whole group (patients with unfavorable karyotypes, 38%; patients with favorable karyotypes, 69%; patients with intermediate karyotypes, 75%) after S-HAM treatment. Importantly, the compression of the 2 induction cycles into the first 11 to 12 days of treatment was beneficial for normal hematopoiesis as demonstrated by a significantly shortened duration of critical neutropenia of 31 days compared with 46 days after conventionally timed double induction.

Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the AMLCG

Chemomodulation of cytarabine by fludarabine has been attributed with a higher antileukemic efficacy, but randomized trials to address this question are rare. We therefore conducted a multicenter, randomized phase III study to evaluate the antileukemic efficacy of adding fludarabine to sequential high-dose cytarabine+idarubicin (SHAI) re-induction chemotherapy in relapsed or refractory acute myeloid leukemia (AML). Patients (n=326, of which 281 were evaluable) were randomly assigned to SHAI (cytarabine, 1 g/m2 bid, days 1–2 and 8–9 (3 g/m2 for patients ⩽60 years with refractory AML or ⩾2nd relapse); idarubicin 10 mg/m2 daily, days 3–4 and 10–11) or F-SHAI (SHAI with fludarabine, 15 mg/m2, 4 h before cytarabine). Although complete remission (CR) rates (35% SHAI and 44% F-SHAI) and overall survival did not differ between both regimens, fludarabine prolonged time to treatment failure from 2.04 to 3.38 months (median, P<0.05). Twenty-seven percent of patients proceeded to allogeneic stem cell transplantation, with a significantly higher number of patients in CR or incomplete remission in the F-SHAI group (22 vs 10%, P<0.01). In conclusion, fludarabine has a beneficial, although moderate, impact on the antileukemic efficacy of high-dose cytarabine-based salvage therapy for relapsed and refractory AML.

Increasing intensity of therapies assigned at diagnosis does not improve survival of adults with acute myeloid leukemia

We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects <60 years were randomized to receive: (1) a first course of induction therapy with high-dose cytarabine and mitoxantrone (HAM) or with standard-dose cytarabine, daunorubicin and 6-thioguanine (TAD) followed by a second course of HAM; (2) granulocyte-colony stimulating factor (G-CSF) or no G-CSF before induction and consolidation courses; and (3) high-dose therapy and an autotransplant or maintenance chemotherapy. In total, 1846 subjects ⩾60 years were randomized to receive: (1) a first induction course of HAM or TAD and second induction course of HAM (if they had bone marrow blasts ⩾5% after the first course); and (2) G-CSF or no G-CSF as above. Median follow-up was 7.4 years (range, 1 day to 14.7 years). Five-year event-free survivals (EFSs) for subjects receiving a first induction course of HAM vs TAD were 17% (95% confidence interval, 15, 18%) vs 16% (95% confidence interval 14, 18%; P=0.719). Five-year EFSs for subjects randomized to receive or not receive G-CSF were 19% (95% confidence interval 16, 21%) vs 16% (95% confidence interval 14, 19%; P=0.266). Five-year relapse-free survivals (RFSs) for subjects <60 years receiving an autotransplant vs maintenance therapy were 43% (95% confidence interval 40, 47%) vs 40 (95% confidence interval 35, 44%; P=0.535). Many subjects never achieved pre-specified landmarks and consequently did not receive their assigned therapies. These data indicate the limited impact of more intensive therapies on outcomes of adults with AML. Moreover, none of the more intensive therapies we tested improved 5-year EFS, RFS or any other outcomes.

Inverted duplication dup(1)(q32q21) as sole aberration in lymphoid and myeloid malignancies

Partial gains of chromosome 1q as isolated aberrations are rare occurrences in hematologic malignancies. A recent report of a sole duplication dup(1)(q21q32) in myelodysplastic syndrome (MDS) suggested an inferior prognosis. To further describe structural anomalies involving the 1q21 and 1q32 breakpoints, we present four cases with an inverted dup(1)(q32q21): three in B-cell precursor acute lymphoblastic leukemia (ALL) and one in MDS of the subtype refractory cytopenia with multilineage dysplasia and ringed sideroblasts. In all four cases, the aberration presented as the sole anomaly at diagnosis. In one of the ALL cases, relapse during chemotherapy, 5 months from diagnosis, was accompanied by clonal evolution; in another ALL case, early relapse appeared 51 days after allogeneic stem cell transplantation. Structural gains of 1q involving 1q32 and 1q21 breakpoints can occur in different hematological malignancies. The isolated occurrence of the inverted dup(1)(q32q21) may be interpreted as a typical primary alteration in B-lineage ALL paving the way to acquisition of additional abnormalities. Identification of more cases could further clarify the role of 1q duplications with the q21 and q32 breakpoints in hematological malignancies and better define the prognosis associated with sole aberration in the single entities.

Biology Oriented Investigation of Treatment Strategies for Acute Myeloid Leukemia (AML): The AMLCG Approach

The outcome in patients with AML appears influenced by some therapeutic variables such as different intensity chemotherapy, growth factor priming, autologous or allogeneic transplantation. Even more than by treatment variables the outcome is determined by genetic and functional features related to the individual disease biology. Open questions are how far these prognostic factors apply to the different treatment options and whether the prognosis in specific subgroups can be improved by specific treatment. We here present a new study strategy using upfront randomization for major treatment alternatives, stratified for de novo versus secondary AML versus MDS, and for their biologic subgroups thus allowing unbiased analyses of subgroup-specific effects by specific treatments.